1. Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
- Author
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Gotts, Jeffrey E, Maishan, Mazharul, Chun, Lauren, Fang, Xiaohui, Han, Chun‐Ya, Chiueh, Venice, Khakoo, Aarif Y, Lee, TaeWeon, Stolina, Marina, and Matthay, Michael A
- Subjects
Emerging Infectious Diseases ,Acute Respiratory Distress Syndrome ,Pneumonia & Influenza ,Lung ,Pneumonia ,Rare Diseases ,Infectious Diseases ,Influenza ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Aetiology ,5.1 Pharmaceuticals ,Infection ,Respiratory ,Angiopoietin-2 ,Animals ,Antibodies ,Neutralizing ,Cells ,Cultured ,Cytokines ,Humans ,Mice ,Mice ,Inbred C57BL ,Orthomyxoviridae ,Pneumonia ,Viral ,Receptor ,TIE-2 ,Viral Load ,angiopoietin-2 ,influenza ,pneumonia ,pulmonary edema ,viral lung injury ,Physiology ,Clinical Sciences ,Medical Physiology - Abstract
Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin-2 (Ang-2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang-2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang-2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang-2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin-1 (Ang-1), Ang-2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post-infection (dpi). We tested a peptide-antibody inhibitor of Ang-2, L1-7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air-liquid interface culture with influenza and measured Ang-2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang-2 lung RNA and a dramatic increase in Ang-2 protein in bronchoalveolar lavage. Inhibition of Ang-2 improved oxygenation and survival and reduced pulmonary edema and alveolar-capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang-2 RNA in human AT2 cells. The increased Ang-2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang-2 antagonism suggest that the Ang-1/Ang-2 Tie-2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.
- Published
- 2021